Vilho Hiilesmaa

Normal intelligence in children with prenatal exposure to carbamazepine

Objective: To investigate the effect of antiepileptic drugs, especially carbamazepine and valproate, on intelligence in prenatally exposed children of mothers with epilepsy. Methods: Intelligence of 182 children of mothers with epilepsy (study group) and 141 control children was tested in a blinded setting at preschool or school age using Wechsler Preschool and Primary Scale of Intelligence–Revised or Wechsler Intelligence Scale for Children–Revised. Data on maternal antiepileptic treatment and seizures during pregnancy were gathered prospectively. The study group represented approximately 50% of the children born to mothers with epilepsy in Uusimaa province during 1989 through1994. One hundred seven children were exposed to antiepileptic monotherapy: 86 to carbamazepine and 13 to valproate. Thirty children were exposed to polytherapy: 23 combinations included carbamazepine, and 17 included valproate. The median maternal doses and blood levels during the second half of pregnancy were 600 mg and 26 μmol/L for carbamazepine and 950 mg and 300 μmol/L for valproate. Results: The mean verbal and nonverbal IQ scores in the children exposed in utero to carbamazepine monotherapy were 96 (95% CI, 93–100) and 103 (95% CI, 100–106). They did not differ from control subjects, whose mean verbal and nonverbal IQ scores were 95 (95% CI, 92–97) and 102 (95% CI, CI, 100–105). Significantly reduced verbal IQ scores were found in children exposed to valproate (mean, 82; 95% CI, 78–87) and to polytherapy (mean, 85; 95% CI, 80–90) compared with the other study group children and control subjects. Conclusions: Carbamazepine monotherapy with maternal serum levels within the reference range does not impair intelligence in prenatally exposed offspring. Exposures to polytherapy and to valproate during pregnancy were associated with significantly reduced verbal intelligence. The independent effects of valproate remain unconfirmed because the results were confounded by low maternal education and polytherapy.

Increased Nuchal Translucency as a Marker for Fetal Chromosomal Defects

BACKGROUND Screening for trisomy 21 (Downs syndrome) by measuring maternal serum alpha-fetoprotein, chorionic gonadotropin, and estriol concentrations and then performing chorionic-villus sampling or amniocentesis identifies approximately 60 percent of fetuses with this disorder. We used ultrasonography to detect increased nuchal translucency and cystic hygroma, which are characteristic features of fetuses with chromosomal defects. METHODS We performed transvaginal ultrasonography in 10,010 unselected adolescents and women less than 40 years of age with live singleton fetuses at 10 to 15.9 weeks of gestation. Increased fetal nuchal translucency was defined as an area of translucency at least 3 mm in width, and cystic hygromas were defined as septated, fluid-filled sacs in the nuchal region. Subjects whose fetuses had these findings were offered fetal karyotyping. Information on pregnancies, deliveries, and neonates was subsequently obtained from hospital records and national birth and malformation registries. RESULTS Nuchal translucency or cystic hygroma was seen in 76 fetuses (0.8 percent), of which 18 (24 percent) had an abnormal karyotype. The sensitivity for trisomies 21, 18, and 13 combined was 62 percent (13 of 21 fetuses), and the sensitivity for trisomy 21 alone was 54 percent (7 of 13 fetuses). CONCLUSIONS The use of transvaginal ultrasonography to detect increased nuchal translucency and cystic hygroma is a sensitive test for fetal aneuploidy. It can be done earlier in pregnancy than serum screening, and it decreases the subsequent need for chorionic-villus sampling or amniocentesis.

Major malformations in offspring of women with epilepsy

Background: The offspring of women with epilepsy are at an increased risk of major congenital malformations, but the impact of the various contributing factors remains unresolved. Method: In 1980 through 1998, the authors prospectively followed up 970 pregnancies in women with epilepsy at a single maternity clinic. Of their 979 offspring, 740 were exposed to maternal antiepileptic drugs (AED) during the first trimester of pregnancy and 239 were not exposed. Maternal AED levels and serum folate concentrations were measured at the end of the first trimester. Logistic regression analysis was applied to identify factors associated with the occurrence of major malformations in the fetuses and newborns. Results: Major malformations were detected in 28 fetuses (3.8%) exposed to maternal AED and in 2 (0.8%) not exposed (p = 0.02). After logistic regression analysis, the occurrence of major malformations was independently associated with use of carbamazepine (adjusted OR 2.5; 95% CI 1.0 to 6.0), use of valproate (4.1; 1.6 to 11), use of oxcarbazepine (10.8; 1.1 to 106), low serum folate concentration (5.8; 1.3 to 27), and low maternal level of education (3.0; 1.3 to 6.8). Major malformations were not associated with seizures during the first trimester (0.6; 0.1 to 2.9). Conclusions: Major malformations in the offspring of mothers with epilepsy are associated with use of AED during early pregnancy, and also with low serum folate concentrations and a low level of education.

Predicting delivery date by ultrasound and last menstrual period in early gestation

Objective To compare last menstrual period and ultrasonography in predicting delivery date. Methods We used ultrasound to scan 17,221 nonselected singleton pregnancies at 8–16 completed weeks. The last menstrual period (LMP) was considered certain in 13,541 and uncertain in 3680 cases. The duration of pregnancy from the scan to the day of spontaneous delivery was predicted by crown-rump length, biparietal diameter (BPD), and femur length (FL) using linear regression models, and the results were compared with estimates based on LMP. Results At all gestational ages, ultrasound was superior to certain LMP in predicting the day of delivery by at least 1.7 days. When deliveries before 37 weeks were excluded, crown-rump length measurement of 15–60 mm (corresponding to 8–12.5 weeks) had the lowest prediction error of 7.3 days. After that time, BPD (at least 21 mm) showed a similar error (7.3 days) and was more precise than crown-rump length. Femur length was slightly less accurate than crown-rump length or BPD. Regression models using a combination of any two or three ultrasonic variables did not improve accuracy of prediction. When ultrasound was used instead of certain LMP, the number of postterm pregnancies decreased from 10.3% to 2.7% (P < .001). Conclusion Ultrasound was more accurate than LMP in dating, and when it was used the number of postterm pregnancies decreased. Crown-rump length of 15–60 mm was superior to BPD, but then BPD (at least 21 mm) was more precise. Combining more than one ultrasonic measurements did not improve dating accuracy.

Objectively measured tobacco exposure during pregnancy: neonatal effects and relation to maternal smoking

Objective To measure quantitatively and objectively the maternal and fetal tobacco exposure during pregnancy and its neonatal effects.

Hyperinsulinemia and Macrosomia in the Fetus of the Diabetic Mother

OBJECTIVE To determine 1) whether macrosomia in the fetus of the diabetic mother is related to fetal hyperinsulinemia and 2) whether hyperinsulinemia and macrosomia are related to maternal metabolic control. RESEARCH DESIGN AND METHODS Normal pregnant women (n = 95) were compared with insulin-treated pregnant women (n = 155), who were subdivided according to Whites class, hypertension, and mode of delivery. All women were treated to achieve optimal metabolic control. HbA1c was determined at each visit. At delivery, umbilical plasma was analyzed for glucose, insulin antibodies, total insulin, free insulin, C-peptide, proinsulin components, and total and individual amino acids. RESULTS Macrosomia, defined as <2 standard deviation units (97.75%), was found in 10–27% of the diabetic groups. It was not related to maternal mass or size, but was significantly correlated with umbilical total insulin, free insulin, and C-peptide. Proinsulin components were not different among groups. Amino acids also were not different. Glycosylated hemoglobin was a weak predictor of birth weight and fetal hyperinsulinism. CONCLUSIONS Macrosomia in the fetus of the diabetic mother remains inadequately explained. In a large population of pregnant women with strict metabolic control, macrosomia was mainly independent of glycosylated hemoglobin. Nevertheless, fetal hyperinsulinism remains the driving force for excessive fetal growth. The stimulus for fetal insulin excess in humans remains to be defined.

Clinical presentation and risk factors of placental abruption

Background. To study the risk factors of placental abruption during the index pregnancy. Methods. One hundred and ninety‐eight women with placental abruption and 396 control women were identified among 46,742 women who delivered at a tertiary referral university hospital between 1997 and 2001. Clinical variables were compared between the groups. Multivariate logistic regression analysis was applied to identify independent risk factors. The clinical manifestations of placental abruption were also studied. Results. The overall incidence of placental abruption was 0.42%. The independent risk factors were maternal (adjusted OR 1.8; 95% CI 1.1, 2.9) and paternal smoking (2.2; 1.3, 3.6), use of alcohol (2.2; 1.1, 4.4), placenta previa (5.7; 1.4, 23.1), pre‐eclampsia (2.7; 1.3, 5.6), and chorioamnionitis (3.3; 1.0, 10.0). Vaginal bleeding (70%), abdominal pain (51%), bloody amniotic fluid (50%), and fetal heart rate abnormalities (69%) were the most common manifestations. Neither bleeding nor pain was present in 19% of the cases. Overall, 59% had preterm labor (OR 12.9; 95% CI 8.3, 19.8), and 91% were delivered by cesarean section (34.7; 20.0, 60.1). Of the newborns, 25% were growth restricted. The perinatal mortality rate was 9.2% (OR 10.1; 95% CI 3.4, 30.1). Retroplacental blood clot was seen by ultrasound in 15% of the cases. Conclusions. Maternal alcohol consumption and smoking, and smoking by the partner turned out to be independent risk factors for placental abruption. Smoking by both partners multiplied the risk. The liberal use of ultrasound examination contributed little to the management of women with placental abruption.

Obstetric outcome in women with epilepsy

A comparison of 150 pregnancies in women with epilepsy and 150 pregnancies in matched nonepileptic control women showed similar rates of pregnancy-induced hypertension, albuminuria, premature contractions, premature labor, and bleeding in pregnancy. Duration of labor, blood loss at delivery, cesarean section rates, and vacuum extraction rates were also similar among epileptic and control groups. There were five perinatal deaths in the epileptic group and two in the control group. A fetal heart rate tracing during a maternal grand mal seizure showed bradycardia, reduced short-term and long-term variability, and late decelerations suggesting asphyxia. It is concluded that grand mal seizures during pregnancy should be avoided by the use of antiepileptic drugs. Women with epilepsy require antenatal neurological and obstetric follow-up during pregnancy.

Fetal heart rate during a maternal grand mal epileptic seizure

Although maternal ingestion of antiepileptic drugs is strongly suspected of causing congenital defects, particularly oral clefts, the effect of epilepsy itself or a combined effect of drug intake and epilepsy have not been excluded as etiological factors. Very little is known about fetal oxygenation during a maternal grand mal epileptic seizure. We describe two cases in which fetal heart rate was recorded during a maternal epileptic seizure during labor. The first fetus became clearly asphyctic as judged from the fetal heart rate recording: immediately after the epileptic seizure there was a 13-minute continuous bradycardia wave with decreased short-term variability. After the bradycardia a phase of tachycardia with decreased short-term and long-term variability occurred. In the other fetus there was only a short period of bradycardia, which was followed by a phase of tachycardia and decreased short-term and long-term variability. Both fetuses were vigorous at birth 43 and 87 minutes, respectively, after the epileptic seizures of their mothers. We conclude that a maternal grand mal epileptic seizure can be ominous to the fetus. It is therefore important that epileptic seizures are controlled by optimal medication throughout pregnancy.

Glycaemic control is associated with pre-eclampsia but not with pregnancy-induced hypertension in women with Type I diabetes mellitus

Aims/hypothesis. To investigate the association between glycaemic control and hypertensive pregnancy complications. Methods. From 1988 to 1997, we followed up 683 consecutive non-selected pregnancies in women with Type I (insulin-dependent) diabetes mellitus. Glycaemic control was assessed by assay of HbA1 c. Pre-eclampsia was defined as diastolic blood pressure of 90 mmHg or more at the end of pregnancy after an increase of 15 mmHg or more, combined with proteinuria of 0.3 g or more for 24 h. Pregnancy-induced hypertension was defined similarly but without proteinuria. The same criteria were applied to a control group of 854 non-selected non-diabetic women. Results. Pre-eclampsia developed in 12.8 % of the women with diabetes (excluding those with nephropathy before pregnancy) and in 2.7 % of the control women (odds ratio 5.2; 95 % CI 3.3–8.4). In multiple logistic regression, glycaemic control, nulliparity, retinopathy and duration of diabetes emerged as statistically significant independent predictors of pre-eclampsia. The adjusted odds ratios for pre-eclampsia were 1.6 (95 % CI 1.3–2.0) for each 1 % increment in the HbA1 c value at 4–14 (median 7) weeks of gestation and 0.6 (0.5–0.8) for each 1 % decrement achieved during the first half of pregnancy. Changes in glycaemic control during the second half of pregnancy did not significantly alter the risk of pre-eclampsia. Unlike pre-eclampsia, the risk of pregnancy-induced hypertension was not associated with glycaemic control. Conclusion/interpretation. In women with Type I diabetes, poor glycaemic control is associated with an increased risk of pre-eclampsia but not with a risk of pregnancy-induced hypertension. [Diabetologia (2000) 43: 1534–1539]